As processes for producing an ascorbic acid derivative wherein the hydroxy group at 2-position is substituted, there have been known, for example, the following processes:
(1) A process wherein, after protecting the hydroxy groups at the 3-, 5- and 6-positions of ascorbic acid, the hydroxy group at the 2-position is substituted and, then, hydrolyzed and/or reduced to obtain the objective ascorbic acid derivative (see, EP-A-O 146 121 and EP-A-O 202 589);
(2) A process wherein, after protecting the hydroxy group at 6-position of ascorbic acid, the hydroxy group at 2-position is substituted, or both hydroxy groups at 2- and 6-positions are substituted, simultaneously [see, Tanaka et al., Yakugaku Zasshi, 86, p. 376 (1966)];
(3) A process wherein, after protecting the hydroxy groups at the 5- and 6-positions of ascorbic acid with an isopropylidene group, the hydroxy group at 2-position is phosphorylated and, then, the isopropylidene groups are removed [Chen H. Lee et al., Carbohydrate Research, 67, 127-138 (1978)];
(4) A process wherein, after protecting the hydroxy groups at the 5- and 6-position of ascorbic acid with isopropylidene, the hydroxy group at 2-position is substituted with sulfonic group and, then, the resultant is subjected to acid hydrolysis to remove the isopropylidene groups [see, Paul A. Seib et al., J. Chem, Soc., Perkin Trans. 1, 1220 (1974)]; and
(5) A process wherein, after protecting the hydroxy group at the 3-position of 5,6-O-isopropylidene ascorbic acid, the hydroxy group at the 2-position is alkylated with an alkyl halide and, then, the resultant is deprotected [see, Kato et al., J. Med. Chem., 31, 793-798 (1988)].
In order to introduce an alkyl group into the 2-position of ascorbic acid to obtain a 2-O-alkylascorbic acid derivative, as a general process, there has been employed a process wherein both the hydroxy groups at 5- and 6-positions are firstly protected to increase solubility in an organic solvent and, then, the hydroxy group at the 3-position which is more acidic and reactive than the hydroxy group at the 2-position is protected, followed by introduction of an alkyl group into the hydroxy group at the 2-position. However, from the industrial point of view, the above process is economically and operationally disadvantageous because the residues which do not constitute the structure of the objective compound are introduced as the protective groups. Further, alkylation at the 2-position with an alkyl halide is accompanied with a side reaction wherein the hydroxy group at the 3-position is also partly alkylated, even if it is protected, which results in insufficient yield.